Epidemiology of Retinopathy and Other Complications in Long Term Type 1 Diabetes Project Summary / Abstract Persons with long term type 1 diabetes mellitus (T1DM) are at high risk of developing severe complications, presenting a pressing need to prevent these outcomes. It is, therefore, the goal of this epidemiological study to determine the relationship of specific underexamined risk factors for these complications that hold promise of diminishing these risks beyond the improvements achieved with current strategies. This study aims to measure advanced glycation endproducts (AGEs), receptors for AGEs (RAGE), carotid intimal-medial thickness, markers of antioxidant stress, and related candidate genes and their relationships to diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, myocardial infarction, stroke, and cognitive dysfunction outcomes. In addition, the study will determine the relationship of retinal vessel diameters and severity of diabetic retinopathy to diabetic nephropathy, diabetic neuropathy, MI, stroke, and cognitive dysfunction. This proposal builds on a longitudinal representative cohort study of persons with long duration of T1DM participating in the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR, funded by NEI grants R01 EY03083 and R01 EY016379). The study included all insulin-taking persons with type 1 diabetes who were receiving primary medical care in an 11-county area of southwestern Wisconsin in 1979- 1980. They were examined in 1980-1982 and approximately every 5 years thereafter. Objective recording of retinopathy from stereoscopic fundus photography combined with a standardized grading, refraction and visual acuity, carotid artery ultrasound, electrocardiogram, measurement of skin intrinsic fluorescence, tests of cognition, and measurement of serum (e.g., AGEs [carboxymethyl lysine, pentosidine], soluble RAGE, oxidized low density lipoprotein cholesterol, creatinine) according to standardized protocols will be obtained in the proposed examination. In addition, we will measure AGEs, RAGE and oxidized low density lipoprotein cholesterol from frozen serum from previous exams to determine longitudinal associations with PDR and other complications. The new data from this study will provide a unique opportunity to determine why, independent of glycemic and blood pressure control, and despite long duration of T1DM, some persons have minimal to mild diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, cognitive dysfunction, and less severe cardiovascular disease, while others have more severe complications. These data will be important to patients and their physicians in developing new interventions for managing type 1 diabetes and to public health practitioners charged with delivering preventive care.